tbuckley/cabot-search huggingface dataset:
Reply to Kamp <i>et al.</i>: Novel Insight into Pulmonary Fibrosis and Long Covid
Authors: Hiroto Hatabu, Kenneth M. Kaye, David C. Christiani
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Reply to: Novel Insight into Pulmonary Fibrosis and Long Covid." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies
Authors: Vasco Lucas, Cláudia Cavadas, Célia Alexandra Aveleira
Journal: Pharmacological Reviews (2023)

An increase in life expectancy in developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers. Also, strategies to prevent the pathologic effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies, and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiologic functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies. <h3>Significance Statement</h3> This paper is an extensive review of what is currently known about the complex process of cellular senescence and explores its most defining features. The main body of the discussion focuses on how the multifeature fluctuation of the senescence phenotype and the physiological role of cellular senescence have both caused a limitation in the search for truly reliable senescence biomarkers and the progression in the development of senotherapies.
Everybody needs good neighbours: the progressive DCIS microenvironment
Authors: Shayin V. Gibson, Reza M. Roozitalab, Michael D. Allen, J. Louise Jones, Edward P. Carter, Richard P. Grose
Journal: Trends in cancer (2023)

Ductal carcinoma in situ (DCIS) is a pre-invasive form of breast cancer where neoplastic luminal cells are confined to the ductal tree. While as many as 70% of DCIS cases will remain indolent, most women are treated with surgery, often combined with endocrine and radiotherapies. Overtreatment is therefore a major issue, demanding new methods to stratify patients. Somewhat paradoxically, the neoplastic cells in DCIS are genetically comparable to those in invasive disease, suggesting the tumour microenvironment is the driving force for progression. Clinical and mechanistic studies highlight the complex DCIS microenvironment, with multiple cell types competing to regulate progression. Here, we examine recent studies detailing distinct aspects of the DCIS microenvironment and discuss how these may inform more effective care.
Is <i>BMAL1</i> Just One Song Impacting the Circadian Dance of Lung Injury?
Authors: Nancy H. Stewart, Isaac Kirubakaran Sundar
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Is BMAL1 Just One Song Impacting the Circadian Dance of Lung Injury?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Novel Insight into Pulmonary Fibrosis and Long COVID
Authors: Jan C. Kamp, Christopher Werlein, Edith K. J. Plucinski, Lavinia Neubert, Tobias Welte, Peter D. Lee, Paul Tafforeau, Claire Walsh, Mark P. Kuehnel, Detlef Schuppan, Marius M. Hoeper, Danny D. Jonigk, Maximilian Ackermann
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

participants moving from relatively low-risk to high-risk subgroups of future diseases, such as chronic obstructive pulmonary disease.As highlighted by Guo and colleagues, and also discussed elsewhere (5), this highlights the importance of taking the heterogeneity of processes that can lead to chronic airway obstruction into account (e.g., bronchopulmonary dysplasia after preterm birth as one specific example) (6).Whether the growth failure group will experience the same (or different) lung aging process as the persistently low group needs to be explored in future studies (7).As pointed out in an accompanying editorial by Custovic and Fontanella (8), the potential respiratory consequences of moving from a higher to a normal group will also have to be explored.Finally, we agree with Guo and colleagues that different trajectory models and predictive scores should be evaluated in different studies and populations to define normal versus abnormal trajectories for clinical use, thus allowing for interventions in those at risk of lung function growth failure and/or accelerated decline.We believe that a life-course approach incorporating genetics with both early and adult life events are, to date, the best alternative to better understand the pathogenesis of chronic respiratory disease through the lifetime (9).
Recent development in multizonal scaffolds for osteochondral regeneration
Authors: Le Yu, Sacha Cavelier, Brett Hannon, Mei Wei
Journal: Bioactive Materials (2023)

Osteochondral (OC) repair is an extremely challenging topic due to the complex biphasic structure and poor intrinsic regenerative capability of natural osteochondral tissue. In contrast to the current surgical approaches which yield only short-term relief of symptoms, tissue engineering strategy has been shown more promising outcomes in treating OC defects since its emergence in the 1990s. In particular, the use of multizonal scaffolds (MZSs) that mimic the gradient transitions, from cartilage surface to the subchondral bone with either continuous or discontinuous compositions, structures, and properties of natural OC tissue, has been gaining momentum in recent years. Scrutinizing the latest developments in the field, this review offers a comprehensive summary of recent advances, current hurdles, and future perspectives of OC repair, particularly the use of MZSs including bilayered, trilayered, multilayered, and gradient scaffolds, by bringing together onerous demands of architecture designs, material selections, manufacturing techniques as well as the choices of growth factors and cells, each of which possesses its unique challenges and opportunities.
Primary Retroperitoneal Lymph Node Dissection for Stage II Seminoma: Is Surgery the New Path Forward?
Authors: Isamu Tachibana, Andre Alabd, Yan Tong, Alex Piroozi, Mohammad Mahmoud, Sean Q. Kern, Timothy A. Masterson, Nabil Adra, Richard S. Foster, Nasser H. Hanna, Lawrence H. Einhorn, Clint Cary
Journal: Journal of Clinical Oncology (2023)

PURPOSE On the basis of National Comprehensive Cancer Network guidelines, clinical stage (CS) II seminoma is treated with radiotherapy or chemotherapy. Primary retroperitoneal lymph node dissection (RPLND) demonstrated recent success as first-line therapy for RP-only disease. Our aim was to confirm surgical efficacy and evaluate recurrences after primary RPLND for CS IIA/IIB seminoma to determine if various clinical factors could predict recurrences. PATIENTS AND METHODS Patients who underwent primary RPLND for seminoma from 2014 to 2021 were identified. All patients had at least 6 months of follow-up. Nineteen patients were part of a clinical trial. Patients receiving adjuvant chemotherapy were excluded from Kaplan-Meier recurrence-free survival (RFS) analysis. RESULTS We identified 67 patients who underwent RPLND for RP-only seminoma. One patient had pN0 disease. Median follow-up time after RPLND was 22.4 months (interquartile range, 12.3-36.1 months) and 11 patients were found to have a recurrence. The 2-year RFS for RPLND-only patients without adjuvant chemotherapy was 80.2%. Patients who developed RP disease for a period &gt; 12 months had the lowest chance of recurrence, with a 2-year RFS of 92.2%. Seven initial CS II patients were on surveillance for 3-12 months before surgery and no patients experienced recurrence. Pathologic nodal stage and high-risk factors such as tumor size &gt; 4 cm or rete testis invasion of the orchiectomy specimen did not affect recurrence. CONCLUSION CS II seminoma can be treated with surgery to avoid rigors of chemotherapy or radiotherapy. Patients with delayed development of CS II disease (&gt; 12 months) had the best surgical results. Patients may present with borderline CS II disease, and careful surveillance may avoid overtreatment. Further study on patient selection and extent of dissection remains uncertain and warrants further investigation.
Genetic profiling analysis design of well-differentiated aggressive grade 2 and 3 gastroenteropancreatic neuroendocrine tumors in the phase III randomized controlled COMPOSE trial.
Authors: Thorvardur Ragnar Halfdanarson, Jaume Capdevila, Daniel M. Halperin, Ken Herrmann, Grace Kong, Simone Leyden, Josh Mailman, Diane Reidy-Lagunes, Rajaventhan Srirajaskanthan, Máté Erdö, Amanda Rotger, Thomas Thevenet
Journal: Journal of Clinical Oncology (2023)

TPS660 Background: Deeper comprehension of gastroenteropancreatic neuroendocrine tumor (GEP-NET) characteristics has led to development of therapeutic interventions such as targeted radionuclide therapies (TRT). In the prospective, randomized, controlled, open-label, multi-center, Phase III COMPOSE trial, the radiolabeled somatostatin analogue 177 Lu-edotreotide will be compared to approved standard of care with everolimus, CAPTEM or FOLFOX in patients with well-differentiated aggressive grade 2 and 3 (Ki-67 index 15−55%), somatostatin receptor positive GEP-NETS. While TRT is advantageous, a key unmet need is to identify additional markers intended to guide patient selection for TRT. This is highly relevant as TRT is a therapy of growing interest likely to be broadly available for patients with variable phenotypes. Profiling analysis as part of COMPOSE plans to analyze the genetic signature of GEP-NETS through full exome sequencing and gene expression analysis of tumor histology and longitudinal blood samples. This analysis may guide detection of pathogenic mutations in NET patients, to potentially inform treatment and surveillance strategies. Methods: Whole exome analysis of tumor-suppressor- and proto-oncogenes included in several pan-cancer panels, upstream and downstream regulators, and novel candidate genes, will be studied. Following patient consent, historical tumor biopsy and blood samples will undergo genetic analysis. Genetic profiling analysis inclusion will not impact trial involvement or disease management. DNA will be assessed to determine the impact of different types of mutations; mRNA will be assessed to confirm and quantify these assumptions and compare gene expression at different treatment phases. Samples will be analyzed in a central pathology laboratory. The aim of this analysis is to develop software that would integrate genetic data with structural and functional imaging, histopathology and phenotype information for implementation into clinical practice. Clinical trial information: NCT04919226 .
Phase I study of PTM-101 as neoadjuvant therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A trial in progress.
Authors: Charles Pilgrim, Marty Smith, Jun Ban, Sam Ellis, John Raymond Zalcberg, Ben Markman, Margaret Lashof-Sullivan, Laura Indolfi
Journal: Journal of Clinical Oncology (2023)

TPS775 Background: While there have been tremendous advances in cancer treatment, critical challenges remain including limited ability of drugs to successfully reach the tumor, short half-life, and low retention rate on site. Local control of non-metastatic pancreatic adenocarcinoma (PDAC) remains a major challenge. Up to 40% of patients present with locally advanced and borderline resectable anatomy, for whom enhanced local downsizing of disease could improve symptoms and increase overall survival (OS). Targeted therapies with reduced systemic toxicity are needed for the treatment of PDAC since current therapies have not provided meaningful advances. PTM-101 is a paclitaxel-impregnated absorbable product which is designed for direct, sustained release of the therapeutic agent at the tumor site. Preclinical animal studies demonstrate that PTM-101 results in enhanced drug levels in the tumor compared with comparable systemic paclitaxel dosing leading to tumor reduction, metastasis inhibition and survival benefit (Indolfi et al, 2016). Large animal (i.e. pigs) and human cadaver studies show that PTM-101 can successfully be deployed to the peritumoral pancreatic surface by a standard laparoscopic procedure. Further, large animal studies show no evidence of neutropenia, pancreatitis, severe fibrosis or scarring, or infection after placement of PTM-101. Methods: This Phase I trial will assess the addition of PTM-101 prior to mFOLFIRINOX in 6 subjects with newly diagnosed borderline resectable or locally advanced PDAC. The primary objective is to assess the safety, toxicity and feasibility of a single administration of PTM-101. It is hypothesized that PTM-101 will be readily implanted during diagnostic laparoscopy and will result in clinically meaningful delivery of paclitaxel directly towards the tumor area with good tolerance and minimal local systemic exposure of drug. Patients enrolled and treated on study will be monitored closely for local and systemic toxicities as well as preliminary signals of efficacy. Enrollment is in progress and 3 patients have been enrolled and completed prospective follow up at the time of abstract submission. Clinical trial information: ACTRN12621000881831 .
A Clinical-Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts
Authors: Andrés Muñoz, Cihan Ay, Ella Grilz, Sonia López, Carme Font, Vanesa Pachón, Victoria Castellón, Virginia Martínez-Marín, Mercedes Salgado, Eva Martínez, Julia Calzas, Laura Ortega, Ana Rupérez, Eduardo Salas, Ingrid Pabinger, Jose Manuel Soria
Journal: Journal of Clinical Oncology (2023)

Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. The Khorana score was developed for assessing the risk of VTE in outpatients with cancer receiving chemotherapy, but its accuracy in identifying patients at high risk has been questioned. The aim of this study was to develop and validate a clinical-genetic score that improves the assessment of VTE risk in oncology outpatients within 6 months of diagnosis.
Tumor microenvironment evaluation to predict anti–PD-1 response of advanced gastric cancer: Results from a multicenter prospective clinical trial.
Authors: Wangjun Liao, Min Shi, Dongqiang Zeng, Huiyan Luo, Jian Xiao, Feng Ye, Hailin Xiong, Xia Yuan, Yisheng Huang, Yongqiang Li, Na Huang, Jianhua Wu, Shaowei Li, Siting Zheng, Jiani Wu, Li Sun, Xiaoxiang Rong, Chunlin Wang, Jian Guo, Qiong Deng
Journal: Journal of Clinical Oncology (2023)

415 Background: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). With the aim of identifying determinants of response, we developed a TMEscore assay (PCR assay with 30 genes) to assess tumor microenvironment, which was previously proved to be a robust predictive biomarker for patients treated with ICBs. Methods: Advanced GC patients treated with ICB combined with chemotherapy as first-line regimen were included in this multi-center prospective clinical trial (NCT#04850716). 65 tumor specimens obtained from 8 medical centers before treatment were applied to estimate TMEscore, PD-L1(CPS) and mismatch repair deficiency (MMR). Of 65 patients, 43 patients with treatment response and 34 patients with progression-free survival (PFS) were used to compare the predictiveness of biomarkers. Results: Theoverall response rate (ORR) and median PFS of this cohort were 39.9% and 4.67 months.Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 61%), but only 16.7% in the low group. Regressive tumors (partial response, PR) had markedly higher TMEscore than stable and progressive tumors (stable disease, SD; progressive disease, PD, P = 0.001). By applying ROC curve analysis, the TMEscore was found to be an encouraging predictive biomarker that surpassed MMR and CPS statistically (AUC = 0.863, 0.525, and 0.519, respectively; Delong test, P = 0.003). Importantly, the Kaplan-Meier survival analysis demonstrated that a high TMEscore was significantly related to a more favorable PFS ( P = 0.0026, HR=0.18, 95%CI 0.06-0.55). Compared to TMEscoreA (immune score), TMEscoreB (stromal score) presented a dramatically higher hazard ratio for PFS (HR = 12.25, P = 0.0001), implicating stromal activation as a critical mechanism of intrinsic resistance to ICB plus chemotherapy. Meanwhile, PD-L1 (CPS) was not statistically associated with PFS, whether 1 or 5 were used as a cutoff to divide patients ( P = 1 and 0.22). Conclusions: This prospective clinical study indicated that the TMEscore assay is a robust biomarker for screening mGC patients who may derive survival benefit from ICB plus chemotherapy. Our data also suggest that TMEscore may be a more accurate predictive biomarker than MSI and CPS (PD-L1) for mGC patients, which warrants additional investigations in larger cohorts. Clinical trial information: NCT#04850716 .
Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis
Authors: Yau-tuen Chan, Hor-yue Tan, Yuanjun Lu, Cheng Zhang, Chien-shan Cheng, Junyu Wu, Ning Wang, Yibin Feng
Journal: Acta Pharmaceutica Sinica B (2023)

Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma (PAAD) patients. Proper regulation could improve survival. Melatonin is an endogenous hormone that delivers multiple bioactivities. Here we showed that pancreatic melatonin level is associated with patients' survival. In PAAD mice models, melatonin supplementation suppressed tumor growth, while blockade of melatonin pathway exacerbated tumor progression. This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils (TANs), and TANs depletion reversed effects of melatonin. Melatonin induced TANs infiltration and activation, therefore induced cell apoptosis of PAAD cells. Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells. Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation. Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype, with increased neutrophil extracellular traps (NETs) causing tumor cell apoptosis through cell-to-cell contact. Proteomics analysis revealed that this reactive oxygen species (ROS)-mediated inhibition was fueled by fatty acid oxidation (FAO) in neutrophils, while FAO inhibitor abolished the anti-tumor effect. Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration. CXCL2, or TANs, combined with NET marker, can better predict patients' prognosis. Collectively, we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.
Author correction to “TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner” [Acta Pharm Sin B 11(12) (2021) 3994–4007]
Authors: Huaqing Zheng, Xiaolong Li, Xin Zeng, Chengcui Huang, Mingming Ma, Xiaofei Lv, Yajuan Zhang, Lu Sun, Guanlei Wang, Yanhua Du, Yongyuan Guan
Journal: Acta Pharmaceutica Sinica B (2023)

[This corrects the article DOI: 10.1016/j.apsb.2021.04.013.].
Association of Elevated Arterial Stiffness With Cardiac Target Organ Damage and Cardiac Autonomic Neuropathy in Young Adults With Diabetes: The SEARCH for Diabetes in Youth Study
Authors: Elaine M. Urbina, Scott Isom, Dana Dabelea, Ralph D’Agostino, Stephen R. Daniels, Lawrence M. Dolan, Giuseppina Imperatore, Eva Lustigova, Santica Marcovina, Amy Mottl, Catherine Pihoker, Amy S. Shah
Journal: Diabetes Care (2023)

OBJECTIVE Adults with diabetes are at risk for cardiovascular (CV) events, possibly due to increased arterial stiffness (AS) and cardiac autonomic neuropathy (CAN). We sought to determine whether 1) AS is associated with cardiac target organ damage in young adults with youth-onset diabetes, 2) whether CAN is associated with AS, as one possible etiology for increased AS in this cohort, and 3) whether these relationships differ by type of diabetes. RESEARCH DESIGN AND METHODS Participants from the SEARCH for Diabetes in Youth Study (type 1 diabetes [T1D], n = 222; type 2 diabetes [T2D], n = 177; mean age 23 years) had clinical, echocardiographic, AS, and CAN assessed. Linear regression was performed to determine whether AS was associated with cardiac changes and CAN and whether relationships differed by diabetes type. RESULTS AS was significantly associated with cardiac structure (left ventricular mass index, P &amp;lt; 0.0001), systolic function (ejection fraction, P = 0.03) and diastolic function (transmitral peak early [E]/atrial [A] wave velocities ratio, P = 0.008; early [e′]/atrial [a′] waves, P = 0.02) after adjustments for CV risk factors. The association between AS and CAN was not significant when other important covariates were added. These relationships were mostly similar in both T1D and T2D. CONCLUSIONS AS is associated with cardiac changes in young adults with diabetes. CAN-induced AS does not appear to be an etiology for cardiac abnormalities in this cohort.